CN104447449A - One-pot method for synthesizing tiamulin - Google Patents
One-pot method for synthesizing tiamulin Download PDFInfo
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- CN104447449A CN104447449A CN201410842597.4A CN201410842597A CN104447449A CN 104447449 A CN104447449 A CN 104447449A CN 201410842597 A CN201410842597 A CN 201410842597A CN 104447449 A CN104447449 A CN 104447449A
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Abstract
The invention discloses a one-pot method for synthesizing tiamulin. According to the method, methylbenzenesulfonate pleuromutilin, diethylamine and ethylene sulfide is subject to an one-pot reaction in a ratio of 1: (1.0 to 1.5) :( 1.0 to 2.0) at room temperature of 50 DEG C to obtain the tiamulin. The method is convenient to operate, low in cost and environment-friendly, and is suitable for industrial production of the tiamulin.
Description
Technical field
The present invention relates to a kind of chemical synthesis process of bulk drug for livestock, be specifically related to a kind of method of one pot process Tiamulin.
Background technology
The chemical structure of Tiamulin is as follows:
Tiamulin is one of ten large veterinary antibiotic, its antimicrobial spectrum is similar to macrolide antibiotics, main resisting gram-positive bacteria, has stronger restraining effect to streptococcus aureus, suis, mycoplasma, actinobacillus pleuropneumoniae, pig treponema dysentery etc.; Macrocyclolactone lactone kind medicine is better than to the effect of mycoplasma.Tiamulin absorbs rapidly in animal body, and Plasma Concentration is high, and distribution in vivo is wide, and residual lower.It is mainly used to prevent and treat chronic respiratory disease, porcine mycoplasmal pneumonia, actinomycetes property pleuropneumonia and treponema dysentery etc.When low dosage uses, can growth of animal be promoted, improve efficiency of feed utilization.This medicine is widely used in the whole world, and is proposed as the choice drug controlling porcine mycoplasmal and infect, the huge market demand.
Tiamulin is a kind of semi-synthetic compound, is to carry out chemically derived forming with the ferment pleuromutilin that obtains of higher fungi pleurotus Pleurotus mutilus basidiomycetes for raw material.Normally first pleuromutilin and Tosyl chloride are reacted obtained p-methyl benzenesulfonic acid pleuromutilin ester (CN 103450057A); This ester carries out nucleophilic substitution reaction again and obtains Tiamulin (CN103450060A) with diethylamino ethanethiol, its synthetic route is as follows:
The subject matter that this method exists price must be used in reaction process high and the diethylamino ethanethiol of difficult purchase, limits the production of Tiamulin.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned Tiamulin synthetic method Problems existing, provides the Tiamulin synthetic method that a kind of environmental friendliness, cost are low, easy and simple to handle.
Solving the problems of the technologies described above adopted technical scheme is: be 1:(1.0 ~ 1.5 by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance): (1.0 ~ 2.0) mix, react under the condition of room temperature to 50 DEG C, obtain Tiamulin, its synthetic route is as follows:
P-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane are preferably 1:(1.0 ~ 1.5 by the ratio of amount of substance by the present invention): (1.0 ~ 2.0) are dissolved in solvent, reaction 2 ~ 24 hours under the condition of room temperature to 50 DEG C, wherein said solvent is any one in ethyl acetate, butylacetate, methyl iso-butyl ketone (MIBK), methyl tertiary butyl ether, glycol dimethyl ether, dimethylbenzene, hexane, sherwood oil.
The present invention is preferred is further that 1:1.5:1.6 is dissolved in solvent by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance, reacts 24 hours at ambient temperature, the preferred glycol dimethyl ether of wherein said solvent.
The present invention is further preferred is that 1:1.5:1.6 is dissolved in solvent by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance, react 4 hours under 50 DEG C of conditions, any one in wherein said solvent ethyl acetate, methyl iso-butyl ketone (MIBK), glycol dimethyl ether.
Raw material p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine and thiirane three directly mix by the present invention, directly synthesized by one pot reaction and obtain Tiamulin, there is the advantages such as easy and simple to handle, with low cost, environmentally friendly, be applicable to the suitability for industrialized production of Tiamulin.
Embodiment
With specific embodiment, the present invention is described in further detail below, but protection scope of the present invention is not limited only to these embodiments.
Embodiment 1
0.532g (1.0mmol) p-methyl benzenesulfonic acid pleuromutilin ester, 1mL ethyl acetate, 155 μ L (1.5mmol) diethylamine, 98 μ L (1.6mmol) thiirane are added in reaction flask, stirring and refluxing 4 hours at 50 DEG C, steam ethyl acetate, residue silica gel column chromatography is separated (moving phase is the volume ratio of ethyl acetate and sherwood oil is the mixture of 1:3), obtain 0.268g Tiamulin, its yield is 54.2%.
Embodiment 2
In embodiment 1, the isopyknic glycol dimethyl ether of ethyl acetate used is replaced, and other steps are identical with embodiment 1, obtains 0.228g Tiamulin, and its yield is 46.1%.
Embodiment 3
In embodiment 1, the isopyknic methyl iso-butyl ketone (MIBK) of ethyl acetate used is replaced, and other steps are identical with embodiment 1, obtains 0.201g Tiamulin, and its yield is 40.6%.
Embodiment 4
In embodiment 1, the isopyknic dimethylbenzene of ethyl acetate used is replaced, and other steps are identical with embodiment 1, obtains 0.177g Tiamulin, and its yield is 35.8%.
Embodiment 5
0.532g (1.0mmol) p-methyl benzenesulfonic acid pleuromutilin ester, 1mL ethyl acetate, 155 μ L (1.5mmol) diethylamine, 98 μ L (1.6mmol) thiirane are added in reaction flask, stirring at room temperature 24 hours, steam ethyl acetate, residue silica gel column chromatography is separated (moving phase is the volume ratio of ethyl acetate and sherwood oil is the mixture of 1:3), obtain 0.187g Tiamulin, its yield is 37.8%.
Embodiment 6
In embodiment 5, the isopyknic glycol dimethyl ether of ethyl acetate used is replaced, and other steps are identical with embodiment 5, obtains 0.266g Tiamulin, and its yield is 53.8%.
Embodiment 7
In embodiment 5, the isopyknic methyl iso-butyl ketone (MIBK) of ethyl acetate used is replaced, and other steps are identical with embodiment 5, obtains 0.161g Tiamulin, and its yield is 32.6%.
Embodiment 8
In embodiment 5, the isopyknic dimethylbenzene of ethyl acetate used is replaced, and other steps are identical with embodiment 5, obtains 0.149g Tiamulin, and its yield is 30.2%.
Embodiment 9
0.532g (1.0mmol) p-methyl benzenesulfonic acid pleuromutilin ester, 155 μ L (1.5mmol) diethylamine, 98 μ L (1.6mmol) thiirane are added in reaction flask, stirring at room temperature 2 hours, with silica gel column chromatography separated product (moving phase is the volume ratio of ethyl acetate and sherwood oil is the mixture of 1:3), obtain 0.066g Tiamulin, its yield is 13.4%.
Claims (6)
1. the method for an one pot process Tiamulin, it is characterized in that: be 1:(1.0 ~ 1.5 by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance): (1.0 ~ 2.0), react under the condition of room temperature to 50 DEG C, obtain Tiamulin.
2. the method for one pot process Tiamulin according to claim 1, it is characterized in that: be 1:(1.0 ~ 1.5 by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance): (1.0 ~ 2.0) are dissolved in solvent, reaction 2 ~ 24 hours under the condition of room temperature to 50 DEG C, wherein said solvent is any one in ethyl acetate, butylacetate, methyl iso-butyl ketone (MIBK), methyl tertiary butyl ether, glycol dimethyl ether, dimethylbenzene, hexane, sherwood oil.
3. the method for one pot process Tiamulin according to claim 2, it is characterized in that: be that 1:1.5:1.6 is dissolved in solvent by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance, react 24 hours at ambient temperature.
4. the method for one pot process Tiamulin according to claim 3, is characterized in that: described solvent is glycol dimethyl ether.
5. the method for one pot process Tiamulin according to claim 2, it is characterized in that: be that 1:1.5:1.6 is dissolved in solvent by p-methyl benzenesulfonic acid pleuromutilin ester, diethylamine, thiirane by the ratio of amount of substance, react 4 hours under 50 DEG C of conditions.
6. the method for one pot process Tiamulin according to claim 5, is characterized in that: described solvent is any one in ethyl acetate, methyl iso-butyl ketone (MIBK), glycol dimethyl ether.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106596784A (en) * | 2016-12-22 | 2017-04-26 | 宁夏泰瑞制药股份有限公司 | Detection method of related substance in tiamulin |
| CN107759502A (en) * | 2017-10-11 | 2018-03-06 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of preparation method of Tiamulin |
| CN113402431A (en) * | 2021-06-18 | 2021-09-17 | 青岛科技大学 | Preparation method of binary system tiamulin by one-pot method |
| CN113735747A (en) * | 2020-05-29 | 2021-12-03 | 新疆上昵生物科技有限公司 | Method for producing tiamulin by using diethylaminoethanethiol synthetic solution |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919290A (en) * | 1972-10-03 | 1975-11-11 | Sandoz Ltd | Substituted 14-desoxy-mutilins |
| BE789629A (en) * | 1971-10-05 | 1973-04-03 | Sandoz Sa | NEW DERIVATIVES OF PLEUROMUTILINE, THEIR PREPARATION AND THERAPEUTIC APPLICATION |
| CN101434567B (en) * | 2008-12-19 | 2012-10-24 | 李扬 | Preparation method of lignocaine ethanethiol |
| CN100593537C (en) * | 2009-02-18 | 2010-03-10 | 赵云现 | Method for synthesizing N,N-diethylin ethanethiol |
| CN102153494B (en) * | 2011-03-04 | 2014-04-30 | 赵云现 | Synthesis technology for N,N-diethylamino group ethanethiol |
| CN103450060A (en) * | 2012-05-29 | 2013-12-18 | 大英九合生物化工股份有限公司 | Synthesis method of tiamulin |
| CN103819374A (en) * | 2012-11-16 | 2014-05-28 | 张丽学 | Process for synthesizing diethylaminoethyl mercaptide |
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2014
- 2014-12-30 CN CN201410842597.4A patent/CN104447449B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106596784A (en) * | 2016-12-22 | 2017-04-26 | 宁夏泰瑞制药股份有限公司 | Detection method of related substance in tiamulin |
| CN106596784B (en) * | 2016-12-22 | 2019-01-29 | 宁夏泰瑞制药股份有限公司 | In relation to the detection method of substance in Tiamulin |
| CN107759502A (en) * | 2017-10-11 | 2018-03-06 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of preparation method of Tiamulin |
| CN107759502B (en) * | 2017-10-11 | 2019-09-10 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of preparation method of Tiamulin |
| CN113735747A (en) * | 2020-05-29 | 2021-12-03 | 新疆上昵生物科技有限公司 | Method for producing tiamulin by using diethylaminoethanethiol synthetic solution |
| CN113402431A (en) * | 2021-06-18 | 2021-09-17 | 青岛科技大学 | Preparation method of binary system tiamulin by one-pot method |
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| CN104447449B (en) | 2016-06-15 |
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